CHAPTER 7. Work-up for Secondary Hypertension: When, why and how much? INTRODUCTION DEFINITION AND CLASSIFICATION. Praveen Jain, Mohammad Jibran

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1 CHAPTER 7 Praveen Jain, Mohammad Jibran Work-up for Secondary Hypertension: When, why and how much? INTRODUCTION Hypertension is one of the most common worldwide diseases afflicting humans and is a major risk factor for stroke, myocardial infarction, vascular disease and chronic kidney disease. Despite extensive research over the past several decades, the etiology of most cases of adult hypertension is still unknown and its control is suboptimal in the general population. Due to the associated morbidity and mortality and cost to society, preventing and treating hypertension is an important public health challenge. Fortunately, recent advances and trials in hypertension research are leading to an increased understanding of the pathophysiology of hypertension and the promise for novel pharmacologic and interventional modalities for this widespread disease. According to the American Heart Association (AHA), approximately 75 million adults in the United States are affected by hypertension. In India, hypertension has significant morbidity and mortality and accounts for nearly 10% of all deaths. Prevalence of hypertension in adults has risen dramatically over the past three decades from 5% to between 20 40% in urban areas and 12 17% in rural areas. The number of hypertensive individuals is anticipated to nearly double from 118 million in 2000 to 213 million by Data from the National Health and Nutrition Examination Survey (NHANES) showed that one in three adults in the US has hypertension, which equates to 29% of the adult population. The prevalence of secondary hypertension in India is 4 5% of all hypertensives. This percentage will continue to increase, primarily because of the aging population. Hypertension is a major contributor to strokes, heart attacks, heart failure, and kidney failure. Primary or essential hypertension accounts for approximately 85% of cases. It is estimated that approximately 15% of hypertensive patients have identifiable conditions causing the blood pressure elevation and may benefit from correction of the underlying disease. 1,2 Data from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), which was released in 2003, was relatively similar to the NHANES data. The JNC 7 noted that approximately 30% of adults were unaware of their hypertension; up to 40% of people with hypertension were not receiving treatment; and, of those treated, up to 67% did not have their BP controlled to less than 140/90 mm Hg. 3 DEFINITION AND CLASSIFICATION Defining abnormally high blood pressure (BP) is extremely difficult and arbitrary. Furthermore, the relationship between systemic arterial pressure and morbidity appears to be quantitative rather than qualitative. A level for high BP must be agreed upon in clinical practice for screening patients with hypertension and for instituting diagnostic evaluation and initiating therapy. Because the risk to an individual patient may correlate with the severity of hypertension, a classification system is essential for making decisions about aggressiveness of treatment or therapeutic interventions.

2 38 Based on recommendations of the JNC 7, the classification of BP (expressed in mm Hg) for adults aged 18 years or older is as follows: 3 Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg. Prehypertension: Systolic mm Hg, diastolic mm Hg. Stage 1: Systolic mm Hg, diastolic mm Hg. Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater. The JNC 8 identifies the following as major cardiovascular risk factors: Hypertension: Component of metabolic syndrome. Tobacco use, particularly cigarettes, including chewing tobacco. Elevated LDL cholesterol (or total cholesterol 200 mg/dl) or low HDL cholesterol: Component of metabolic syndrome. Diabetes mellitus: Component of metabolic syndrome. Obesity (BMI 30 kg/m 2 ): Component of metabolic syndrome. Age >55 years for men or >65 years for women: Increased risk begins at the respective ages; the Adult Treatment Panel III used earlier age cut points to suggest the need for earlier action. Estimated glomerular filtration rate less than 60 ml/ min. Microalbuminuria. Family history of premature cardiovascular disease (men <55 years; women <65 years). Lack of exercise. The JNC 8 report released in December 2013, recommends less aggressive target blood pressure and treatment initiation threshold than the JNC 7 for elderly patients and in patients younger than 60 years with diabetes and kidney disease, and no longer recommends just thiazide/thiazide-type diuretics as initial therapy in most patients. 4,5 In essence, the JNC 8 recommends treating 150/90 mm Hg in patients over age 60 years; for everybody else, the goal BP is 140/90. 5 Especially severe cases of hypertension or hypertensive crises are defined as a BP of more than 180/120 mm Hg and may be further categorized as hypertensive emergencies or hypertensive urgencies. From another perspective, hypertension may be categorized as either Primary (essential) or Secondary. Primary hypertension is diagnosed in the absence of an identifiable secondary cause. Approximately 90 95% of adults with hypertension have primary hypertension, whereas secondary hypertension accounts for around 5 10% of the cases. 6 However, secondary forms of Section 2: Hypertension and Dyslipidemia hypertension, such as primary hyperaldosteronism, account for 20% of resistant hypertension (hypertension in which BP is >140/90 mm Hg despite the use of medications from 3 or more drug classes, 1 of which is a thiazide diuretic). Secondary hypertension has been encountered with increasing frequency. Secondary hypertension by definition is a type of hypertension which is caused by an identifiable underlying potentially correctable disease. Secondary hypertension can be caused by a renal disease (renal parenchymal 2 3% and renovascular 1 2%), endocrinal diseases like pheochromocytoma, primary aldosteronism (Conn syndrome, Cushing s syndrome) ( %), oral contraceptives (0.5%) and others 0.5%. Renal causes constitute the largest group. Takayasu s syndrome (progressive aortoarteritis) is the most common cause of renovascular hypertension in India. The detection of a secondary cause is of the utmost importance because it provides an opportunity to convert a lifelong incurable disease into a potentially curable one. Early identification and treatment will provide a better opportunity for cure, prevent target organ damage, reduce socioeconomic burden and health expenditure associated with drug cost and will also improve patient s quality of life. Hence, it is a condition not to be missed. APPROACH CONSIDERATIONS In general, the evaluation of hypertension primarily involves accurately measuring the patient s blood pressure on several different occasions. Home/ambulatory BP monitoring may be of great help. Equally important is performing a focused medical history, physical examination, obtaining results of routine laboratory studies and selected specialized tests to exclude possible secondary causes (Table 1). These steps can help determine the following: 3,4 Presence of end-organ disease Possible causes of hypertension Associated cardiovascular risk factors Baseline values for judging biochemical effects of therapy. In an analysis of 4388 patients enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prediction model based on Framingham Heart Study criteria was better than prehypertension at identifying young adults who went on to develop new hypertension in the following 25 years. The concordance index (c-index) for incident hypertension was 0.84 using the Framingham prediction model and 0.71 using prehypertension. 7,8 Criteria used in the CARDIA prediction model included age, sex, body mass index (BMI), smoking, systolic blood

3 Chapter 7: Work-up for Secondary Hypertension: When, why and how much? 39 Table 1 Signs and symptoms that suggest specific causes of secondary hypertension Signs/symptoms Arm to leg systolic blood pressure difference >20 mm Hg Delayed or absent femoral pulses Murmur Increase in serum creatinine concentration ( mg/dl [ µmol/l]) after starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Renal bruit Bradycardia/tachycardia Cold/heat intolerance Constipation/diarrhea Irregular, heavy, or absent menstrual cycle Possible secondary hypertension cause Coarctation of the aorta Renal artery stenosis Thyroid disorders Diagnostic test options Magnetic resonance imaging (adults) Transthoracic echocardiography (children) Computed tomography angiography Doppler ultrasonography of renal arteries Magnetic resonance imaging with gadolinium contrast media Thyroid-stimulating hormone Hypokalemia Aldosteronism Renin and aldosterone levels to calculate aldosterone/renin ratio Apneic events during sleep Daytime sleepiness Snoring Flushing Headaches Labile blood pressures Orthostatic hypotension Palpitations Sweating Syncope Buffalo hump Central obesity Moon facies Striae Obstructive sleep apnea Pheochromocytoma Cushing s syndrome Polysomnography (sleep study) Sleep apnea clinical score with night-time pulse oximetry 24-hour urinary fractionated metanephrines Plasma-free metanephrines 24-hour urinary cortisol Late-night salivary cortisol Low-dose dexamethasone suppression pressure (BP), and parental history of hypertension. Prehypertension was defined as systolic BP mm Hg or diastolic BP mm Hg. Patients may have undiagnosed hypertension for years without having had their BP checked. Therefore, a careful history of end-organ damage should be obtained. The JNC 8 identifies the following as targets of end-organ damage: Heart: Left ventricular hypertrophy, angina/ previous myocardial infarction, previous coronary revascularization and heart failure. Brain: Stroke or transient ischemic attack, dementia. Chronic kidney disease. Peripheral arterial disease. Retinopathy. The historical and physical findings that suggest the possibility of secondary hypertension are a history of known renal disease, abdominal masses, anemia, and urochrome pigmentation. A history of sweating, labile hypertension, and palpitations suggests the diagnosis of pheochromocytoma. A history of cold or heat tolerance, sweating, lack of energy, and bradycardia or tachycardia may indicate hypothyroidism or hyperthyroidism. A history of obstructive sleep apnea may be noted. A history of weakness suggests hyperaldosteronism. Kidney stones raise the possibility of hyperparathyroidism. Age considerations are also important as etiologies vary according to different age groups (Table 2). Renal artery stenosis (RAS) can be due to either an atherosclerotic process or fibromuscular dysplasia, both of which will result in hypertension. The American College of Cardiology/American Heart Association (ACC/ AHA) guidelines on peripheral arterial disease agree that screening for RAS is only indicated if a corrective procedure would be considered if clinically significant renovascular disease was detected. 9,10 The gold standard for diagnosing RAS is renal arteriography; however, it remains unsuitable for screening as it is invasive and expensive. A variety of less invasive tests have been evaluated for screening purposes. 11,12 False negative tests are the major concern with all noninvasive tests, since patients with a potentially correctable cause of hypertension will be missed. Noninvasive imaging with

4 40 Table 2 Common causes of secondary hypertension by age group* Age groups Children (birth to 12 years) Adolescents (12 18 years) Young adults (19 39 years) Middle-aged adults (40 64 years) Older adults (65 years and older) Percentage of hypertension with an underlying cause renal magnetic resonance angiography (MRA) or CT has been used. MRA is promising and noninvasive. However, it has been validated only for the stenosis situated in the proximal cm of renal arteries. Distal RAS and segmental RAS were generally not analysed. The sensitivity of MRA was 90% for proximal RAS, 82% for main RAS and 0% for segmental stenosis. Moreover, these methods only provide anatomical information about RAS and do not document whether a stenosis is severe enough to cause a pressure gradient, triggering renin release and subsequent renovascular hypertension. At present, there is no sufficiently accurate, noninvasive radiologic or serologic screening test that, if negative, will completely exclude the presence of RAS. 13,14 Thus, the clinical index of suspicion and the presence or absence of renal insufficiency are the primary determinants of the degree and type of evaluation. PHYSICAL EXAMINATION An accurate measurement of blood pressure is the key to diagnosis. Several determinations should be made over a period of several weeks. At any given visit, an average of Section 2: Hypertension and Dyslipidemia Most common etiologist Renal parenchymal disease Coarctation of the aorta Renal parenchymal disease Coarctation of the aorta 5 Thyroid dysfunction Fibromuscular dysplasia Renal parenchymal disease 8 12 Aldosteronism Thyroid dysfunction Obstructive sleep apnea Cushing syndrome Pheochromocytoma 17 Atherosclerotic renal artery stenosis Renal failure Hypothyroidism *Excluding dietary and drug causes and the risk factor of obesity. Listed in approximate order of frequency within groups 3 blood pressure readings taken 2 minutes apart using a mercury manometer is preferable. 3,4 On the first visit, blood pressure should be checked in both arms and in one leg to avoid missing the diagnosis of coarctation of aorta or subclavian artery stenosis. The patient should rest quietly for at least 5 minutes before the measurement. Blood pressure should be measured in both the supine and sitting positions, auscultating with the bell of the stethoscope. As the improper cuff size may influence blood pressure measurement, a wider cuff is preferable, particularly if the patient s arm circumference exceeds 30 cm. Although somewhat controversial, the common practice is to document phase V (a disappearance of all sounds) of Korotkoff sounds as the diastolic pressure. Ambulatory or home blood pressure monitoring provides a more accurate prediction of cardiovascular risk than do office blood pressure readings. 15 Nondipping is the loss of the usual physiologic nocturnal drop in blood pressure and is associated with an increased cardiovascular risk. A study by Wong and Mitchell indicated that independent of other risk factors, there is a link between the presence of certain signs of hypertensive retinopathy (e.g. retinal hemorrhages, microaneurysms, cotton-wool spots) and an increased cardiovascular risk (e.g. stroke, stroke mortality). 16 Therefore, a fundus examination should be performed to detect any evidence of early or late, chronic or acute hypertensive retinopathy, including arteriovenous nicking or changes in the vessel wall (e.g. copper wiring, silver wiring, SOT, hard exudates, flameshaped hemorrhages, papilledema). Indeed, ocular changes can be the initial finding in an asymptomatic patient necessitating a primary care referral; acute and chronic changes may manifest in the eyes. Alternatively, a symptomatic patient may be referred to the ophthalmologist for visual changes due to hypertensive changes. Palpation of all peripheral pulses should be performed. Absent, weak, or delayed femoral pulses suggests coarctation of the aorta or severe peripheral vascular disease. In addition, examine the neck for carotid bruits, distended veins, or enlarged thyroid gland. Listen for renal artery bruit over the upper abdomen; the presence of a bruit with both a systolic and diastolic component suggests renal artery stenosis. A careful cardiac examination is performed to evaluate signs of LVH. These include displacement of apex, a sustained and enlarged apical impulse, and the presence of an S4. Occasionally, a tambour S2 is heard with aortic root dilatation.

5 Chapter 7: Work-up for Secondary Hypertension: When, why and how much? 41 BASELINE LABORATORY EVALUATION Initial Work-up Initial laboratory tests may include urinalysis; fasting blood glucose or A1C; hematocrit; serum sodium, potassium, creatinine (estimated or measured glomerular filtration rate [GFR]), and calcium; and lipid profile following a 9- to 12-hour fast (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides). An increase in cardiovascular risk is associated with a decreased GFR level and with albuminuria. 3 A resting 12 lead ECG is also done routinely. Assessment of Suspected Secondary Causes Other studies may be obtained on the basis of clinical findings or in individuals with suspected secondary hypertension and/or evidence of target-organ disease, such as complete blood count (CBC), chest radiograph, uric acid, and urine microalbumin. 3 Microalbuminuria is an early indication of diabetic nephropathy and is also a marker for a higher risk of cardiovascular morbidity and mortality. Recommendations suggest that individuals with type I diabetes should be screened for microalbuminuria. Usefulness of this screening in hypertensive patients without diabetes has not been established. 17 Measurement of the ratio of aldosterone to plasma renin activity (PRA) is performed to detect evidence of primary hyperaldosteronism. A ratio of more than is suggestive of this condition. Most antihypertensive medications can falsely raise or lower this ratio; thus, an appropriate washout period is necessary to obtain an accurate aldosterone-renin ratio. At what point hypokalemia manifests in primary hyperaldosteronism could be debated. The consideration of the underlying secondary cause of hyperaldosteronism is primarily driven by hypokalemia, especially that which is unprovoked or represents an exaggerated hypokalemic response to a thiazide. It is important to note that aldosterone levels can be falsely low in the presence of hypo kalemia. Hypokalemia and metabolic alkalosis are relatively late manifestations of primary hyperaldosteronism. A 24 hour urine specimen should be collected for sodium and potassium measurement. If the urine sodium level is >100 mmol/l and urine potassium is <30 mmol/l, hyperaldosteronism is unlikely. If urinary potassium exceeds 30 mmol/l, the patient should have plasma renin activity measured. If the PRA is high, the likely cause is estrogen therapy, renovascular hypertension, malignant hypertension, or salt-wasting renal disease (or blockade of the renin-angiotensin system the far more common reason). In the presence of low PRA, the serum aldosterone level can be measured (aldosterone and renin should be measured together; separate measurements will lead to inaccuracy). A low aldosterone level indicates licorice ingestion or other mineralocorticoid ingestion. A high aldosterone level indicates primary hyperaldosteronism. A computed tomography scan may identify the presence of an adenoma. In the absence of CT scan findings, differentiating hyperplastic hyperaldosteronism from adenoma is often difficult. Determination of a sensitive thyroid-stimulating hormone (TSH) level excludes hypothyroidism or hyperthyroidism as a cause of hypertension. If pheochromocytoma is suspected, urinary cate cholamines and fractionated metanephrines are the tests of choice. Plasma fractionated metanephrines have specificity, but their sensitivity is too low for screening purposes. Urinary vanillylmandelic acid (VMA) is no longer recommended because of its poor sensitivity and specificity. CONCLUSION Secondary hypertension is a common cause of hypertension in adults, occurring in about 10% of hypertensive patients. High index of suspicion is most important to identify secondary hypertension. Detailed medical history, thorough physical examination, and appropriate laboratory tests are particularly pertinent in the early identification of these reversible, potentially curable conditions (Flow chart 1). Failure to recognize secondary causes can lead to resistant hypertension, cardiovascular complications or complications of the underlying condition. In younger adults (<30 years of age), renal causes such as glomerulonephritis and coarctation of the aorta should be considered. In older adults, primary aldosteronism, RAS and OSA are common and often underdiagnosed. Screening tests, if available, should be performed to detect these conditions. Endocrine hypertension has emerged as a common cause of secondary hypertension, particularly after the recognition that primary aldosteronism accounts for 5 10% of hypertensive cases. Early identification and treatment will provide a better opportunity for cure, prevent complications related to hypertension, reduce cost pertaining to lifelong antihypertensive usage or hospitalizations and lead to an improvement in the quality of life of these patients. Secondary hypertension should not be missed.

6 42 Section 2: Hypertension and Dyslipidemia Flow chart 1 Algorithmic approach to the initial evaluation of patient with suspected secondary hypertension Abbreviations: MRI, magnetic resonance imaging; CT, computed tomography; TSH, thyroid-stimulating hormone * If not done as part of initial evaluation Choice of renal artery imaging modality based on availability, institutional expertise and patient factors REFERENCES 1. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275(20): Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2011;42:517e Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6): James PA, Oparil S, Carter BL, et al Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, Wood S. JNC 8 at last! Guidelines ease up on BP thresholds, drug choices. Heartwire, Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, JAMA. 2003;290(2): Stiles S. Framingham Criteria Predict New Hypertension Better Than Prehypertension in Young Adults. Medscape Medical News. Available at view article/ Carson AP, Lewis CE, Jacobs DR Jr, Peralta CA, Steffen LM, Bower JK, et al. Evaluating the Framingham Hypertension Risk Prediction Model in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. Hypertension, Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Practice Guidelines for the management of patients with peripheral

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